rs17882942

chr22-28689143-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_007194.4(CHEK2):c.1534C>G(p.Leu512Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,593,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L512P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 0.151

Genes affected

CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039534003).
• BP6: Variant 22-28689143-G-C is Benign according to our data. Variant chr22-28689143-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141856.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1534C>G	p.Leu512Val	missense_variant	14/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1534C>G	p.Leu512Val	missense_variant	14/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000856 AC: 20 AN: 233624 Hom.: 0 AF XY: 0.0000623 AC XY: 8 AN XY: 128318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 24 AN: 1441464 Hom.: 0 Cov.: 29 AF XY: 0.0000153 AC XY: 11 AN XY: 717720

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ExAC AF: 0.0000435 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 18, 2023	In the published literature, this variant has been reported in individuals affected with breast cancer (PMID: 21244692 (2011), 25186627 (2015), 31206626 (2019)), colorectal cancer ((PMID: 28944238 (2017)) as well as in unaffected individuals (PMID: 31206626 (2019)). This variant was characterized as benign based on an in vivo yeast-based functional assay (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.0006 (21/35204 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: normal growth in response to DNA damage (Delimitsou et al., 2019); Observed in individuals with a personal history of breast cancer (Le Calvez-Kelm et al., 2011; Tung et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21244692, 26787654, 27527004, 16671833, 25186627, 31398194, 31106920, 30851065) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2017	Variant summary: The CHEK2 c.1534C>G (p.Leu512Val) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution in the protein kinase domain (InterPro). 5/5 in silico tools predict benign outcome for this variant. This variant was found in 5/113850 control chromosomes including broad and large population from ExAC at a frequency of 0.0000439, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). However, it was only found in Latino subpopulation with an allele frequency of 0.000452 (5/11054 chromosomes) which is nearly 1.5 times the estimated maximal expected allele frequency, possibly suggesting that it is a rare population-specific polymorphism. However, in a case-control study, this variant was found in one breast cancer patient but not in controls (Calvez-Kelm_2011). Pathogenic variants in this gene are associated with elevated risk of breast cancer. Whether this variant is a significant risk allele needs to be further investigated. To our knowledge, the variant has not been tested by in vitro/in vivo functional assays. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is currently classified as VUS-possibly benign. -

Familial cancer of breast Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 512 of the CHEK2 protein (p.Leu512Val). This variant is present in population databases (rs17882942, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 21244692, 25186627). ClinVar contains an entry for this variant (Variation ID: 141856). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 29, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 11, 2023	The p.L512V variant (also known as c.1534C>G), located in coding exon 13 of the CHEK2 gene, results from a C to G substitution at nucleotide position 1534. The leucine at codon 512 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer and in controls across studies (Le Calvez-Kelm F et al. Breast Cancer Res., 2011 Jan;13:R6; Young EL et al. J. Med. Genet., 2016 06;53:366-76; Weitzel JN et al. Cancer. 2019 08;125(16):2829-2836). This variant was also reported in a cohort of 1231 colorectal cancer cases (DeRycke MS et al. Mol Genet Genomic Med. 2017 Sep;5(5):553-569). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration was also reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is poorly conserved in available vertebrate species. In addition, this missense alteration is predicted to be tolerated by in silico analysis, but In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 28, 2016	- -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C1836482:Li-Fraumeni syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	4.8
Dann	Benign	0.47
DEOGEN2	Benign	0.079	T;.;T;.;T;.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.075	N
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.040	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;.;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.040	N;N;N;.;N;N;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.84	T;T;T;.;T;T;.;T;T
Sift4G	Benign	0.50	T;T;T;.;T;T;.;T;T
Polyphen		0.0	B;B;B;.;B;B;B;B;B
Vest4		0.16
MutPred		0.083		Loss of catalytic residue at L512 (P = 0.0229);.;Loss of catalytic residue at L512 (P = 0.0229);.;Loss of catalytic residue at L512 (P = 0.0229);.;Loss of catalytic residue at L512 (P = 0.0229);.;.;
MVP		0.38
MPC		0.020
ClinPred		0.025	T
GERP RS		2.9
Varity_R		0.071
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17882942; hg19: chr22-29085131;